Laboratory Tests to Determine the Cause of Hypokalemia and Paralysis

ORIGINAL INVESTIGATION Laboratory Tests to Determine the Cause of Hypokalemia and Paralysis

Shih-Hua Lin, MD; Yuh-Feng Lin, MD; Dung-Tsa Chen, PhD; Pauling Chu, MD, PhD; Chin-Wang Hsu, MD; Mitchell L. Halperin, MD

Background: Hypokalemia and paralysis may be due tients in the non-HPP group had urine potassium con- to a short-term shift of potassium into cells in hypoka- centration values less than 20 mmol/L. Although the po- lemic periodic paralysis (HPP) or due to a large deficit tassium concentration was significantly lower in the HPP of potassium in non-HPP. Failure to make a distinction group, there was some overlap. In contrast, the transtu- between HPP and non-HPP may lead to improper man- bular potassium concentration gradient and potassium- agement. Therefore, we evaluated the diagnostic value creatinine ratio differentiated patients with HPP vs non- of spot urine tests in patients with hypokalemia and pa- HPP. Although only a mean±SD of 63±36 mmol of ralysis during 3 years. potassium chloride was administered in the patients with HPP, rebound hyperkalemia (Ͼ5 mmol/L) occurred in Methods: Before therapy, the urine potassium concen- 19 (63%) of these 30 patients. tration, potassium-creatinine ratio, and transtubular potassium concentration gradient were determined in a sec- Conclusions: Calculating the transtubular potassium ond voided urine sample. concentration gradient and potassium-creatinine ratio provided a simple and reliable test to distinguish HPP from Results: Forty-three patients with hypokalemia and pa- non-HPP. Minimal potassium chloride supplementa- ralysis were identified: 30 had HPP and 13 had non- tion should be given to avoid rebound hyperkalemia in HPP. There was no significant difference in the plasma patients with HPP. potassium or bicarbonate concentrations and in the pH of arterial blood between the 2 groups. All but 2 pa- Arch Intern Med. 2004;164:1561-1566

YPOKALEMIA AND PARALY- been misdiagnosed as having HPP.9 Be- sis (HP) is a potentially cause hypokalemia is the primary bio- reversible medical emer- chemical abnormality in patients with HP, gency.1 Morbidity and measurements of the urinary excretion of mortality are related to potassium were the focus of our evalua- complicationsH secondary to hypokalemia tion. To establish whether renal potas- such as a cardiac arrhythmia or respira- sium wasting is present in these medical tory failure.2 Although there are many po- emergencies, one cannot wait for a pro- tential causes of hypokalemia, there are far longed, timed urine collection. Hence, a From the Division of fewer entities in the differential diagno- second voided spot urine collection be- Nephrology, Department of sis of HP (Table 1).1 Hypokalemia and fore initiation of therapy is the optimum Medicine (Drs S. H. Lin, Y. F. Lin, and Chu), and paralysis can be divided into 2 types, hy- sample to examine. In this study, we Department of Emergency pokalemic periodic paralysis (HPP) due to sought to evaluate the diagnostic value of 3-5 Medicine (Dr Chen), a short-term shift of potassium into cells spot urine tests in patients with HP. Tri-Service General Hospital, and non-HPP resulting from a large defi- National Defense Medical cit of potassium.6,7 Center, Taipei, Taiwan; The differential diagnosis in a pa- METHODS Biostatistics Unit, UAB tient with HP can be challenging, but it is Comprehensive Cancer Center, important to make the diagnosis promptly STUDY SUBJECTS University of Alabama, because different therapies are required for Birmingham (Dr Hsu); and each type. Although some features dis- The study protocol was approved by the Eth- Renal Division, St Michael’s ics Committee on Human Studies at Tri- Hospital, University of Toronto, cerned on patient history such as a posi- Service General Hospital, Taiwan. Taipei, In- Toronto, Ontario tive family history or a recurrent episode formed consent was obtained from each patient. (Dr Halperin). The authors can be helpful, the clinical features of HPP Forty-three new patients with HP were en- have no relevant financial and non-HPP are almost indistinguish- rolled in this study between January 1, 2000, interest in this article. able.8 Many patients with non-HPP have and December 31, 2002. Hypokalemia and pa-

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Downloaded From: https://jamanetwork.com/ on 09/28/2021 Table 1. Patient Characteristics and Final Diagnosis

No. of Age, Patient Group Patients Mean ± SD, y Male-Female Hypokalemic periodic paralysis (n = 30) Thyrotoxic periodic paralysis 20 28 ± 8 20:0 Sporadic periodic paralysis 9 28 ± 7 8:1 Familial periodic paralysis 1 19 1:0 Non–hypokalemic periodic paralysis (n = 13) Primary aldosteronism 1 34 1:0 Gitelman syndrome 4 24 ± 2 3:1 Licorice ingestion 1 72 1:0 Distal renal tubular acidosis 5 38 ± 23 2:3 Fanconi syndrome with proximal renal tubular acidosis 1 42 1:0 Profound diarrhea 1 47 1:0

ralysis was defined as an acute loss of muscle power with an ANALYTICAL TECHNIQUES inability to ambulate and a plasma potassium concentration that was less than 3 mmol/L on presentation. The paralysis tended Arterial blood gases were measured by an ABL 510 (Radiometer, to involve the muscles of the extremities and limb girdles. Copenhagen, Denmark). Biochemical values, including serum and urine creatinine, urea nitrogen, albumin, total calcium, inor- DEFINITIONS ganic phosphate, magnesium, sodium, potassium, and chloride, were determined by automated methods (AU 5000 chemistry ana- Hypokalemic Periodic Paralysis lyzer; Olympus, Tokyo, Japan). Plasma osmolality (Posm) and urine osmolality (Uosm) were measured by freezing-point depression (Ad- Hypokalemic periodic paralysis must be defined on clinical grounds. vanced Instruments Inc, Needham Heights, Mass). There were 4 elements to the diagnosis. First, a positive family history, recurrent clinical pattern, or evidence of hyperthyroid- CALCULATIONS ism made HPP a likely diagnosis. The absence of the intake of agents that could cause a shift of potassium into cells was also The transtubular potassium concentration gradient (TTKG) was important in this context. Second, if there was no indication of calculated as previously described ([urine/plasma 10 other diseases known to be associated with potassium wasting, potassium]/[urine/Posm]). It is not physiologically valid to cal- 11 again HPP would be suspected. Third, if the patients required less culate the TTKG if the Uosm is less than the Posm. The urine than 1.5 mmol of potassium chloride per kilogram of body weight potassium-creatinine ratio, an index of the potassium excre- to return their plasma potassium concentration to the normal tion rate, was calculated using their respective concentrations range, this supported the diagnosis of HPP. Fourth, the absence in millimoles per liter. of an acid-base disorder strengthened the diagnosis of HPP.9 STATISTICAL ANALYSIS Non–Hypokalemic Periodic Paralysis The mean±SD was calculated for patient characteristics and Non–hypokalemic periodic paralysis was suspected if none of the diagnostic measures. A 2-sample t test was used to compare 4 findings in the previous paragraph were present, if there was the differences in diagnostic measures, recovery times, and an explanation for a large deficit of potassium, if more than 3 amount of potassium chloride that was administered in mmol/kg of potassium was needed to correct the plasma po- the HPP and non-HPP groups. Scatterplots were used for tassium concentration to the normal range, and if an acid-base data visualization to explore the cutoff values for diagnostic disorder was present.9 measures.

PROCEDURES RESULTS A spot urine sample was collected before therapy by self- voiding if possible or with a Foley catheter if the patient was Forty-three patients with a severe degree of hypokale- unable to urinate. To avoid the possibility of obtaining urine mia (range, 1.5-2.6 mmol/L) and paralysis were in- that represented a mixture of urine from before the onset of cluded in the study. The male-female ratio was 38:5; their the attack and at the time of the attack, urine in the bladder on ages ranged from 18 to 78 years. Of the 43 patients, 30 presentation was discarded and a second voided urine speci- were in the HPP group and 13 in the non-HPP group. men was collected during the next hour. An arterial blood sample The mean age (28±8 vs 37±18 years) and body mass in- was collected in all the patients; venous blood samples were dex (calculated as weight in kilograms divided by the collected through an indwelling catheter. All of the patients re- square of height in meters) (22.0±2.3 vs 21.5±2.1) were ceived intravenous potassium chloride administration at a rate not significantly different between the 2 groups. In the of 10 mmol/h until muscle strength had recovered and the pa- HPP group, 20 patients had thyrotoxic periodic paraly- tient could ambulate. The plasma potassium concentration was sis (TPP) (Table 1). Three known dihydropyridine- measured hourly during the attack and for 6 hours after recov- ␣ ery. The recovery time was defined as the time required from sensitive calcium channel 1 subunit (CACNA1S) gene the initiation of potassium chloride therapy to the recovery of mutations (R528H, R1239H, and R1239G) were ana- sufficient muscle strength to ambulate. The quantity of potas- lyzed in the patients with TPP, sporadic periodic paraly- sium chloride administered was recorded. sis (SPP), and familial periodic paralysis (FPP). The pa-

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Downloaded From: https://jamanetwork.com/ on 09/28/2021 Table 2. Biochemical Study Results on Admission in Patient Groups*

Study Reference Range Hypokalemic Periodic Paralysis Non–Hypokalemic Periodic Paralysis Plasma pH 7.35-7.45 7.39 ± 0.03 7.39 ± 0.12 Sodium, mmol/L 135-142 142 ± 2 141 ± 3 Potassium, mmol/L 3.5-5.0 2.0 ± 0.3 1.9 ± 0.2 Chloride, mmol/L 98-106 106 ± 2 105 ± 6 Bicarbonate, mmol/L 22.0-26.0 24.0 ± 1.6 25.0 ± 8.8 Phosphate, mmol/L 0.8-1.5 0.7 ± 0.2 0.8 ± 0.2 Magnesium, mmol/L 0.7-1.0 0.8 ± 0.1 0.7 ± 0.2 Glucose, mmol/L 4.0-7.0 8.2 ± 0.9 7.7 ± 1.2 Urea nitrogen, mmol/L 3.0-7.0 5.0 ± 1.4 6.1 ± 1.8† Creatinine, mmol/L 0.06-0.10 0.08 ± 0.02 0.09 ± 0.02† Urine Potassium, mmol/L NA 9 ± 3 15 ± 4‡ Creatinine, mmol/L NA 6.8 ± 2.8 3.7 ± 1.2‡ Urine osmolality, mOsm/kg NA 598 ± 165 363 ± 105‡ Urine osmolality-creatinine ratio, mOsm/mmol NA 94 ± 20 100 ± 16 Potassium-creatinine ratio, mmol/mmol NA 1.3 ± 0.1 4.1 ± 0.2‡ Transtubular potassium concentration gradient NA 2.1 ± 0.5 6.0 ± 1.2‡

Abbreviation: NA, not applicable. Conventional conversion factors: To convert to milligrams per deciliter, divide creatinine by 88.4, glucose by 0.0555, magnesium by 0.411, and urea nitrogen by 0.357. *Data are given as mean ± SD. †PϽ.05. ‡PϽ.001.

tient with FPP had an R528H point mutation. Only one there was a need for other supportive evidence to con- patient with SPP had a de novo mutation (R528H). None firm that non-HPP was the likely diagnosis. of the patients with TPP had mutations in the 3 hot spots. When examining the spot urine samples, the Uosm The major causes of disease in the non-HPP group and creatinine concentration were significantly higher in were Gitelman syndrome (GS) (n=4) and distal renal tu- the HPP group compared with the non-HPP group bular acidosis (n=5). The diagnosis of GS was based on (PϽ.001) (Table 2). These were likely to be unreliable the following criteria: hypokalemia of renal origin with indexes because there was no significant difference in the renal potassium wasting, hypomagnesemia of renal ori- Uosm-creatinine ratio, indicating comparable daily os- gin, and hypocalciuria with a urine calcium-creatinine mole excretion rates but higher water intakes in the non- ratio less than 0.1 mmol/mmol. Mutations in the thiazide- HPP group. Although the mean urine potassium con- sensitive sodium chloride cotransporter (NCC) gene were centration was significantly lower in patients with HPP found in 3 of 4 patients. These included a homozygous vs non-HPP (9±3 [range, 3-15] vs 15±4 [range, 11-21] mutation with H90M in the first patient, compound het- mmol/L; PϽ.001), all but 2 patients in the non-HPP group erogeneous mutations with T60M and R642C in the sec- had values less than 20 mmol/L. Furthermore, there were ond patient, and compound heterogeneous mutations with overlapping urine potassium concentration values in the T163M and N426K in the third patient.12 The diagnosis HPP and non-HPP groups (Figure 1). Hence, the urine of distal renal tubular acidosis was based on the find- potassium concentration is not reliable to discriminate ings of normal anion gap metabolic acidosis associated between these 2 entities. One patient with HPP and 2 pa- with minimal ammonium excretion and a urine pH greater tients with non-HPP had a Uosm that was less than the Posm, than 6.0. Sjo¨gren syndrome was present in 4 of the 5 pa- invaliding the TTKG calculation.11 Nevertheless, the mean tients with distal renal tubular acidosis. TTKGs (2.1 ± 0.5 [range, 1.2-3.0] vs 6.0 ± 1.2 [range, 4.5- The biochemical values in plasma and urine are 8.5]; PϽ.001) were sufficiently different in every other shown in Table 2. There were no significant differ- case to help differentiate between HPP and non-HPP cat- ences in the mean plasma potassium concentrations be- egories (Figure 2). The urine potassium-creatinine ra- tween the 2 groups (2.0±0.3 [range, 1.5-2.6] vs 1.9±0.2 tio (mean, 1.3±0.1 [range, 0.6-2.3] vs 4.1±0.2 [range, [range, 1.5-2.3] mmol/L). The plasma creatinine and urea 2.6-5.8] mmol/mmol; PϽ.001) was helpful in differen- nitrogen concentrations were lower in patients with HPP tiating between HPP and non-HPP in every case (PϽ.05), but these differences were small. Although ab- (Figure 3). The diagnostic cutoff values for the TTKG normal acid-base values were helpful to identify pa- and the potassium-creatinine ratio were 3.0 mmol/ tients with non-HPP, at times the results of this initial mmol and 2.5 mmol/mmol, respectively. blood test were equivocal. For example, the lowest plasma The mean quantities of potassium chloride admin- bicarbonate concentration at the time of admission was istered up to the time of recovery were 63±36 mmol 25 mmol/L (pH 7.43) in the metabolic alkalosis sub- (range, 20-180 mmol) in the HPP group vs 171±44 mmol group, and the highest plasma bicarbonate concentra- (range, 90-260 mmol) in the non-HPP group. Rebound tion was 18 mmol/L (pH 7.35) in this subgroup. Hence, hyperkalemia (plasma potassium concentration, Ͼ5

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Downloaded From: https://jamanetwork.com/ on 09/28/2021 sium excretion rates measured in 24-hour urine samples.13 25 Hypokalemic Periodic A urine potassium concentration that is less than 15 to Paralysis Non–Hypokalemic 20 mmol/L or less than 15 to 20 mmol/d suggests that 20 Periodic Paralysis there is an extrarenal cause for potassium depletion. Hy- pokalemia in the setting of levels exceeding these values 15 indicates that there is a renal cause for potassium wasting.14,15 Obtaining a 24-hour potassium excretion rate is 10 not practical in a medical emergency because therapy with potassium chloride must be given promptly. A spot urine 5 collection before potassium chloride therapy is the speci- men that should be used to help establish the diagnosis. Urine Potassium Concentration, mmol/L Three urinary indexes of renal response to hypoka- 01234 lemia were studied: spot urine potassium concentra- Plasma Potassium Concentration, mmol/L tion, TTKG, and potassium-creatinine ratio. Although all 3 indexes have been used previously, their ability to dis- Figure 1. Plasma and urine potassium concentrations in the patient cohort. tinguish between HPP and non-HPP has never been evaluated in an emergency department setting, to our knowl-

10 edge. In this study, the spot urine potassium concentration Hypokalemic Periodic Paralysis was significantly lower in the HPP group than the non- Non–Hypokalemic HPP group; however, there were many overlapping val- 8 Periodic Paralysis ues because polyuria is common in patients with hypokalemia (Figure 1). The polyuria may be due to thirst or 6 defective renal concentration in patients with chronic hypokalemia; this leads to a low value for the urine potas- 4 sium concentration even if significant renal potassium wasting is present.16,17 This is likely part of the explana- 2 tion why 11 (85%) of the 13 patients in this study with non-HPP had spot urine potassium concentration val-

Transtubular Potassium Concentration Gradient Transtubular ues that were less than 20 mmol/L in the presence of ex- 01234 Plasma Potassium Concentration, mmol/L cessive renal potassium wasting. Therefore, a more reliable test is required. Figure 2. Transtubular potassium concentration gradients in the patient The TTKG is a semiquantitative index for events in cohort. the lumen of the cortical collecting ducts, because it ad- justs for the plasma potassium concentration and for water reabsorption in the medullary collecting ducts.11,18 7 Hypokalemic Periodic Although calculating the TTKG is a reliable way to dis- Paralysis 6 Non–Hypokalemic tinguish between HPP and non-HPP, a TTKG is invalid Periodic Paralysis 10 if the Uosm is lower than the Posm in a patient. In our study, 5 1 patient with HPP and 2 with non-HPP had a Uosm that 4 was less than the Posm. In these patients, one must rely on another index of potassium excretion to establish the 3 diagnosis. 2 The other variable reflecting potassium excretion, the potassium-creatinine ratio, has been used to evalu- 1 ate the cause of hypokalemia; it is based on a near- 19,20

Urine Potassium-Creatinine Ratio, mmol/mmol constant rate of creatinine excretion. Although the rate 01234 of creatinine excretion can affect the potassium-creatinine Plasma Potassium Concentration, mmol/L ratio, none of the patients with HPP had a low body mass index, which might have produced a lower rate of cre- Figure 3. Urine potassium-creatinine ratios in the patient cohort. atinine excretion and thereby a misleading elevated value for the potassium-creatinine ratio in the urine. If a pa- mmol/L) after recovery developed in 19 of 30 patients tient has a reduced muscle mass, this should be consid- in the HPP group, with a mean peak plasma potassium ered in interpretation of the results. The potassium- concentration of 5.6±0.4 mmol/L; hypokalemia per- creatinine ratio also was useful to differentiate between sisted in the patients with non-HPP (mean, 2.7±0.2 HPP and non-HPP; the diagnostic cutoff value for the po- mmol/L). tassium-creatinine ratio was approximately 2.5 mmol/ mmol. In our patients, the body mass index and timed COMMENT creatinine excretion rates were similar in patients with HPP and non-HPP. The traditional approach to distinguishing between ex- The rate of potassium excretion is thought to be low trarenal and renal causes of hypokalemia is based on spot if gastrointestinal loss of potassium is the presumed cause urine potassium concentration values or urine potas- of hypokalemia.21 Nevertheless, 1 patient in our study

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Potassium Excretion Rate (TTKG, Urine Potassium-Creatinine Ratio) Acid-base Disorder

TTKG <3.0 or Urine Potassium- TTKG >3.0 or Urine Potassium- Creatinine Ratio <2.5 mmol/mmol Creatinine Ratio >2.5 mmol/mmol

Shift Deficit

Clue Acid-base State

Family Hyperthyroidism No History

Familial Thyrotoxic Sporadic Metabolic Acidosis Metabolic Alkalosis Periodic Periodic Periodic Paralysis Paralysis Paralysis Ammonium Excretion Blood Pressure (UAG, UOG)

High Low Normal High

Toluene Abuse Renal Urine Urine Mineralocorticoid-like Chloride↓ Chloride↑ Profound Diarrhea Tubular Excess State Acidosis Vomiting Diuretics Renin Gitelman Aldosterone Syndrome Renin↓ Renin↓ Bartter Aldosterone↑ Aldosterone↓ Syndrome Primary Licorice Ingestion Aldosteronism Ectopic Corticotropin Apparent Mineralocorticoid Excess Syndrome Liddle Syndrome

Figure 4. Algorithm for an approach to patients with hypokalemia and paralysis in the emergency department. UAG indicates urine anion gap (sodium+potassium−chloride); UOG, urine osmolar gap ([measured−calculated] osmolality/2); and TTKG, transtubular potassium concentration gradient.

had non-HPP due to profound diarrhea; her potassium- rebound hyperkalemia (Ͼ5 mmol/L) occurred in 19 (63%) creatinine ratio and TTKG were high, suggesting that re- of 30 patients with HPP, although only a mean of 63 mmol nal potassium wasting was also present. Because many was administered before recovery. This result suggests that patients experiencing diarrhea with hypokalemia have potassium chloride supplements in patients with HPP low fecal potassium excretion, fecal losses cannot ex- should be minimal to prevent rebound hyperkalemia. In plain the entire potassium deficit.22 Secondary hyperal- contrast, in patients with non-HPP, excessive renal po- dosteronism caused by circulating volume depletion re- tassium excretion required therapy with much more po- sulting from fecal sodium loss may lead to an increased tassium (mean, 170 mmol) to reverse the paralysis; re- urine potassium concentration excretion and play a con- bound hyperkalemia did not occur. In cases of severe tributory role in the development of hypokalemia.22 Other potassium depletion (400-500 mmol), this amount of po- factors, including metabolic alkalosis with bicarbonatu- tassium supplementation should be provided.27 ria, hypomagnesemia, and intrinsic renal disorders, may To confirm the etiology of HPP, genetic studies were be involved in renal potassium wasting during certain di- carried out because clinical neuromuscular presenta- arrheal states.22,23 tions in TPP and SPP are indistinguishable from FPP, in With respect to therapy, vigorous potassium re- which an ion channel abnormality in skeletal muscle is placement has been advocated for the treatment of pa- involved. Thyrotoxic periodic paralysis and SPP were sug- ralysis and prevention of a fatal cardiac arrhythmia in pa- gested to be ion channelopathies.28 In this study, we ex- tients with HPP.24,25 However, the effectiveness of this amined 3 hot spots (R528H, R1239H, and R1239G) for therapeutic approach is questionable because there is no HPP. The patient with FPP had an R528H point muta- correlation between the dose of potassium chloride ad- tion, and only one patient with SPP had a de novo mu- ministered and recovery time.1 Furthermore, spontane- tation (R528H). However, none of the patients with TPP ous recovery from paralytic attacks with subsequent nor- had mutations in the 3 hot spots, consistent with a re- malization of the plasma potassium concentration occurs cent report by Dias da Silva and colleagues.29 This sug- in some patients with HPP who do not receive potas- gests that mutations linked to FPP in CACNA1S may be sium replacement.6 shared with SPP but not with TPP. Gene analysis of other Failure to distinguish HPP from non-HPP may lead calcium, sodium, or potassium channels should be ex- to overly aggressive treatment of an apparent potassium amined in patients with TPP with CACNA1S to deter- deficit, with rebound hyperkalemia on recovery. In ret- mine whether common ion channel defects are in- rospective studies by Manoukain26 and Lin9 and col- volved in TPP. leagues, rebound hyperkalemia occurred in 30% to 42% Thirty-one percent (4/13) of patients with non- of patients with HPP, especially if more than 90 mmol of HPP had GS, an inherited renal electrolyte disorder mainly potassium chloride was given within 24 hours. In our study, due to mutations in the thiazide-sensitive sodium chlo-

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Downloaded From: https://jamanetwork.com/ on 09/28/2021 ride cotransporter.30 The degree of hypokalemia is usu- 6. Huang YY, Hsu RS, Tsai JS. Paralytic myopathy: a leading clinical presentation ally mild to moderate. Recently, however, more patients for primary aldosteronism in Taiwan. J Clin Endocrinol Metab. 1996;81:4038- 4041. with GS have been found with a degree of hypokalemia that 7. Dowd JE, Lipsky PE. Sjo¨gren’s syndrome presenting as hypokalemic periodic is similar to that in patients with Bartter syndrome with so- paralysis. Arthritis Rheum. 1993;36:1735-1738. dium-potassium-chloride cotransporter (NKCC2) and chlo- 8. Ahlawat SK, Sachdev A. Hypokalemic paralysis. Postgrad Med J. 1999;75:193- ride channel (ClC-Kb) gene mutations.31 As reported by 197. 32 9. Lin SH, Lin YF, Halperin ML. Hypokalemia and paralysis. QJM. 2001;94:133- Cruz el al, approximately 6% of patients with GS pre- 139. sent with HP. Many patients in Asia with GS present with 10. West ML, Bendz O, Chen CB, et al. Development of a test to evaluate the trans- paralysis related to profound hypokalemia.10,33,34 tubular potassium concentration gradient in the cortical collecting duct in vivo. The limitation of this study was that we had a small Miner Electrolyte Metab. 1986;12:226-233. number of patients with non-HPP. Nevertheless, we iden- 11. Ethier JH, Kamel KS, Magner PO, Lemann J Jr, Halperin ML. The transtubular potassium concentration in patients with hypokalemia and hyperkalemia. Am J tified a cost-effective, rapid, safe, and reliable bedside tool Kidney Dis. 1990;15:309-315. to differentiate HPP from non-HPP. A prospective study 12. Cheng NL, Kao MC, Hsu YD, Lin SH. Novel thiazide-sensitive Na-Cl cotrans- is needed to validate the diagnostic value of using spot porter mutation in a Chinese patient with Gitelman’s syndrome presenting as hy- urine samples in emergency situations. pokalaemic paralysis. Nephrol Dial Transplant. 2003;18:1005-1008. 13. Narins RG, Jones ER, Stom MC, Rudnick MR, Bastl CP. Diagnostic strategies in disorders of fluid, electrolyte and acid-base homeostasis. Am J Med. 1982;72: CONCLUSIONS 496-520. 14. Weiner ID, Wingo CS. Hypokalemia: consequences, causes and correction. JAm In conjunction with plasma acid-base values, an appro- Soc Nephrol. 1997;8:1179-1188. priate index of potassium excretion helps distinguish the 15. Gennari FJ. Hypokalemia. N Engl J Med. 1998;339:451-458. 16. Berl T, Linas SL, Aisenbrey GA, Anderson RJ. On the mechanism of polyuria in diagnostic categories of HPP from non-HPP. The TTKG potassium depletion: the role of polyuria. J Clin Invest. 1977;60:620-625. and urine potassium-creatinine ratio are useful esti- 17. Marples D, Frokiaer J, Dorup J, Knepper MA, Nielsen S. Hypokalemia-induced mates of the potassium excretion process. However, the down-regulation of aquaporin-2 water channel expression in rat kidney medulla and cortex. J Clin Invest. 1996;97:1960-1968. TTKG is invalid if the Uosm is less than the Posm; the po- 18. West ML, Marsden PA, Richardson RMA, Zettle RM, Halperin ML. New clinical tassium-creatinine ratio is independent of the Uosm. Urine approach to evaluate disorders of potassium excretion. Miner Electrolyte Metab. potassium-creatinine ratios less than 2.5 mmol/mmol and 1986;12:234-238. TTKGs less than 3.0 in hyperosmolar urine were reli- 19. Halperin ML, Kamel KS. Electrolyte quintet: potassium. Lancet. 1998;352:35-40. able cutoff values to differentiate between patients with 20. Kamel KS, Ethier JH, Richardson RM, Bear RA, Halperin ML. Urine electrolytes HPP and non-HPP. A diagnostic flowchart is provided and osmolality: when and how to use them. Am J Nephrol. 1990;10:89-102. 21. Elisaf M, Siamopoulos KC. Fractional excretion of potassium in normal subjects to illustrate our approach to HP in the emergency de- and in patients with hypokalemia. Postgrad Med J. 1995;71:211-212. partment (Figure 4). In patients with HPP, the dose of 22. Agarwal R, Afzalpurkar R, Fordtran JS. Pathophysiology of potassium absorp- potassium chloride supplementation should be mini- tion and secretion by the human intestine. Gastroenterology. 1994;107:548- mal (Ͻ10 mmol/h) to avoid rebound hyperkalemia. 571. 23. Kim HJ, Yoon YM, Park KN. The change in electrolytes and acid-base after arti- ficially induced acute diarrhea by laxatives. J Korean Med Sci. 1994;9:388-393. Accepted for publication October 31, 2003. 24. Conway MJ, Seibel JA, Eaton RP. Thyrotoxicosis and periodic paralysis: im- This study was supported by grant 91-2314-B-016- provement with beta blockage. Ann Intern Med. 1974;81:332-336. 093 from the National Science Council, Taipei. 25. Kodali VRR, Jeffcote B, Clague RB. Thyrotoxic periodic paralysis: a case report We thank Kamel S. Kamel, MD, for his critique of the and review of the literature. J Emerg Med. 1999;17:43-45. 26. Manoukian MA, Foote JA, Crapo LM. 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